Gradient Coatings with Biopolymer-resistant domains

ABSTRACT

A medical device or analytical device comprising a fluid-impervious surface comprising a base surface, at least one distinct region of the base surface covered by a mixed monolayer film, the mixed monolayer film comprising a species having a functional group Ml and a species having a functional group M2 where M1 and M2 have different surface energies, the mixed monolayer forming a surface energy gradient wherein at least one of the species used to form the monolayer on the surface comprises a biopolymer-resistant domain.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of and claims the benefit of U.S.application Ser. No. 12/803,576 filed Jun. 30, 2010 which is acontinuation of U.S. application Ser. No. 10/494,122 filed Aug. 12, 2004(now U.S. Pat. No. 7,790,265) which is the National Phase of PCTApplication PCT/US02/35134 filed Nov. 1, 2002 which claims priority toprovisional application 60/335,165 filed Nov. 1, 2001, the contents ofSer. No. 10/494,122 is herein incorporated by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

PARTIES TO A JOINT RESEARCH AGREEMENT

Not Applicable.

FIELD OF THE INVENTION

This invention relates to a surface-energy gradient on afluid-impervious surface and method of its creation.

BACKGROUND OF THE INVENTION

Microscopic fluidic devices, ranging from surgical endoscopes andmicroelectromechanical systems to the commercial ‘lab-on-a-chip’, allowchemical analysis and synthesis on scales unimaginable a few decades ago(Kataoka and Troian, 1999). Advances in micro fabrication techniqueshave led to the ability to manufacture flow channels ranging from a fewhundred angstroms to a few hundred microns (Pfahler, et al, 1990).However, due to the microscopic scale of the systems involved, fluidtransport and friction losses are problematic. Different methods usingtemperature, pressure, or electric potential gradients have beendeveloped to transport fluid through these systems. Each of thesemethods increases the energy required to operate such systems, and noneof the methods solve the problem of fluid friction losses.

Friction arises from the adhesive forces between two surfaces in contactIn the absence of wear and plastic deformation, as is the case in fluidtransport in microscale systems, friction is largely attributable tointerfacial effects (Krim, 1996). For laminar flow in channels, fluidfriction loss (f) can be estimated as

f=16/Rewhere Re=Reynolds Number (ρ v DC/μ)ρ=density of fluidv=fluid velocityDc=effective diameter of channelμ=viscosity of fluid

Therefore, as Dc begins to approach micron and angstrom dimensions,friction loss increases greatly.

Organic thin films have been used to control friction and wear in avariety of machines. As machines get even smaller, and lubricating filmsapproach the monolayer regime, self-assembled monolayer films show greatpotential for use in such items. SAM films have been shown to reduce thefriction between two surfaces. By changing the energy of the surface,the SAM can prevent a fluid such as water from wetting the surface. Areduction in the attraction between the fluid and the tail group of theSAM will result in a reduction in friction.

Several studies have been conducted on the frictional properties ofSAMs. These studies have shown how friction varies depending on thestructure and composition of the SAM. Most of these studies used AtomicForce Microscopy (AFM) to measure friction. This measurement isperformed by passing the AFM probe tip over the SAM surface. Thefrictional response of the surface is measured by the AFM as the normalforce exerted by the probe is varied. In their 1996 paper, Xiao et aldetermined how the chain length of the SAM affected friction. Their workwith mica surfaces showed that longer-chain SAMs reduce friction themost. Longer chain molecules form films that are typically more denselypacked and more crystalline in structure than shorter chain moleculesdo. The enhanced crystalline structure and better packing provide alower friction surface (Liu and Evans, 1996). Their work with SAM filmson gold surfaces led to the same conclusions regarding chain length andcrystalline structure.

The effect of the tail group was then studied. Researchers determinedthat frictional behavior closely followed the variation of the adhesiveproperties, meaning low-energy surfaces had the lowest friction whilehigh-energy surfaces such as —NH2 produced higher amounts of frictionloss (Tsukruk and Bliznyuk, 1998). Kim et al in 1999 found that amonglow energy surfaces, those with the smallest head group yielded thesurface with the lowest friction. Specifically, CF3-terminated films hadthree times the friction of CH3-terminated films.

In addition to lowering the friction between two surfaces, SAMs can havea dramatic effect on the ability of a fluid to wet a surface. Forinstance, CH3-terminated SAMs produce low energy, hydrophobic surfacesthat are not wet by water while CO2H-terminated SAMs produce highenergy, hydrophilic surfaces that are almost completely wet by water.The contact angle that water forms with a surface is a good indicationof the surface's hydrophilicity or hydrophobicity. For instance, waterforms a contact angle of 115° with CH3 surfaces while it forms a contactangle of <15° with CO 2H surfaces. In general, as the contact angledecreases, water has more affinity for the surface and will more easilywet it (Laibinis et al, 1998).

A system that reduced friction losses and improved fluid transport wouldhave a great benefit.

All US patents and applications and all other published documentsmentioned anywhere in this application are incorporated herein byreference in their entirety.

Without limiting the scope of the invention a summary of some of theclaimed embodiments of the invention is set forth below. Additionaldetails of the summarized embodiments of the invention and/or additionalembodiments of the invention may be found in the Detailed Description ofthe Invention below.

A brief abstract of the technical disclosure in the specification isprovided as well only for the purposes of complying with 37 C.F.R. 1.72.The abstract is not intended to be used for interpreting the scope ofthe claims.

SUMMARY OF THE INVENTION

The proposed system uses self-assembled monolayer (SAM) films to modifya surface; a novel design is proposed which modifies the surface using amixed SAM surface so that fluids are transported with minimal or reducedexternal forces required. The proposed design will result inmicrofabricated systems that are smaller and more energy-efficient.

In one embodiment a method of derivatizing a fluid-impervious surfacewith a mixed monolayer to create a surface energy gradient comprises thefollowing steps:

a) exposing a base surface having a proximal and a distal portion to afirst solution comprising a plurality of molecules of the formulaX1-J1-M1, wherein X1 and M1 represent separate functional groups and J1represents a spacer moiety that, together, are able to promote formationfrom solution of a self-assembled monolayer for sufficient time to forma monolayer surface having a substantially uniform surface energy on thebase surface,b) removing a portion of the monolayer of step (a) such that a portionof the base surface is again fully or partially exposed,c) exposing the portion of the base surface from (b) to a secondsolution comprising a plurality of molecules of the formula X2-J2-M2 anda plurality of molecules of the formula X1-J1-M1 wherein the functionalgroup M2 has a different surface energy from that of the functionalgroup M1 such that a surface energy gradient from a proximal location toa distal location is formed.

In another embodiment, removing a portion of the monolayer is done whilethe base surface and monolayer surface are immersed in either the firstsolution or the second solution.

In another embodiment removal of a portion of the monolayer of (a) isperformed using a method or combination of methods selected from thegroup consisting of 1) passing an instrument along the monolayer surfacecreated in (a) with sufficient force to remove a portion of themonolayer created in (a), 2) etching chemically the portion to beremoved, 3) etching physically the portion to be removed, 4) cuttingwith a laser, 5) cutting with water, 6) etching through thermometricexposure, 7) removing with grit, 8) drilling, 9) sonic means, and 10)cutting with an instrument.

These and other embodiments which characterize the invention are pointedout with particularity in the claims annexed hereto and forming a parthereof. However, for a better understanding of the invention, itsadvantages and objectives obtained by its use, reference should be madeto the drawings which form a further part hereof and the accompanyingdescriptive matter, in which there are further embodiments of theinvention illustrated and described.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a blown-up schematic view of the method for producinga mixed monolayer surface energy gradient;

FIG. 2 illustrates a blown-up schematic view of the method during theremoval and exposure steps wherein the instrument that removes the SAMlayer also delivers new molecules to the surface;

FIG. 3 illustrates a blown-up schematic view of the method during theremoval and exposure steps wherein the instrument that removes the SAMlayer also delivers mixture to the surface;

FIG. 4 illustrates a blown-up schematic view of the method during theremoval and exposure steps wherein the instrument that removes the SAMlayer also delivers new molecules to the surface which are mixed in anoutside reservior.

FIG. 5 illustrates a schematic view of the end condition for arepresentative method for reacting a mixed monolayer to incorporate agradient of other chemical species. In this figure the portions of theCH₃—CO₂H mixed monolayer that do not take part in the reaction are notshown (e.g. CH₃).

FIG. 6 illustrates a side elevational view of a method for creating agradient along the walls of the tube in a direction along a longitudinalaxis through the center of the tube.

FIG. 7 illustrates a side elevational view of a method for creating agradient on the walls of the tube in a strip formed by rotating theinstrument about the longitudinal axis through the center of the tube.

FIG. 8 illustrates a schematic view of a spiral surface energy gradientthat might be produced on the inside of a tube when the movements ofFIG. 6 and FIG. 7 are combined.

FIG. 9 illustrates a side elevational schematic view of a method forcreating a gradient along the outside walls of the tube.

FIG. 10 illustrates a cross-sectional schematic view of the tube andinstrument in which the instrument has at least one tip used in themethod for creating a surface energy gradient on the interior of thetube.

FIG. 11 illustrates a cross-sectional schematic view of the tube andinstrument in which the instrument has at least one tip used in themethod for creating a surface energy gradient on the outside of thetube.

DETAILED DESCRIPTION OF THE INVENTION

While this invention may be embodied in many different forms, there aredescribed in detailed herein specific preferred embodiments of theinvention. This description is an exemplification of the principles ofthe invention and is not intended to limit the invention to theparticular embodiments illustrated.

As used herein, the term “tube” is any hollow object open on two sideswithout limitation by cross-sectional geometries.

Turning now to the drawings, FIG. 1 shows a blown-up schematic view ofan embodiment of the method for producing a mixed monolayer surfaceenergy gradient. The view consists of 6 slides. Slide (a) shows a basesurface 1 having a monolayer 3. The original monolayer is made up of aplurality of first organic molecules 5. The base surface 1 having amonolayer 3 can be stored and used later as well. The first organicmolecules 5 are comprised of a functional group 7 (e.g. thiol) thatreacts with the base surface 1 and a low surface energy functional group9 (e.g. CH₃, CF₃, etc). The instrument 11 is not in contact with themonolayer 3 at this point of the process. The instrument 11 in slide (b)comes into contact with the monolayer 3 and removes some of the originalmonolayer 3 as the instrument 11 passes along the surface 1. At the sametime, second organic molecules 13 are added. The second organicmolecules 13 are comprised of a functional group 7 designed to reactwith the base surface 1 and a high surface energy functional group 17(e.g. OH, CO₂H, CONH₂, etc). Slide (c) shows how some of the secondorganic molecules 13 are reacting with the base surface 1 and creating amixed SAM layer. As shown in slide (d), this process continues as theinstrument 11 continues along the base surface 1. More second organicmolecules 13 are being added and are reacting with the exposed basesurface 1. This continues through slide (e) and in slide (f) a higherconcentration of high energy groups 17 make up the monolayer 3 and alongthe portion of the surface the instrument 11 passed, a surface energygradient 19 is formed.

Unlike prior art examples, the surface energy gradient of this inventionis designed to be formed with well-defined dimensions that correspond tothe features of the instrument used in the process. The length (L) ofthe gradient will correspond to the length of the path traced by theinstrument while the width (W) of the gradient will correspond to thewidth or radius of the instrument tip used to expose the base layer.Thus, a very long and thin gradient region can be created with thismethod with aspect ratios (length divided by width, L/W) that can varyfrom 2.0, 10.0, to essentially an infinite number. Nanografting using anAtomic Force Microscope (AFM) as the instrument will produce surfaceenergy gradients with very small width dimensions. As an example, AFMinstruments with a tip radius of 20-nm could be used in the invention(Liu and Evans, p. 1236, col. 2). Using this instrument, a surfaceenergy gradient region of 20 nm wide by 1000 nm long could be created;such a region would have an aspect ratio of 50. Gradients with higheraspect ratios (10,000 or greater) can be created by increasing the pathlength traced by the instrument. High aspect ratio gradient regionscould also be made using AFMs with tip radii in the 40-500 nm to producegradient regions with a larger width W (Tsukruk and Bliznyuk, p.448,col. 1). Other instruments such as those commonly used in micromachiningapplications can be used. Micromachining applications are capable ofusing manufacturing channels with widths in the 100-1000 micron rangewhile standard machining techniques can produce channels with widths inthe 1.0-10.0-mm range.

In one embodiment a method of derivatizing a fluid-impervious surfacewith a mixed monolayer to create a surface energy gradient comprises thefollowing steps:

a) exposing a base surface having a proximal and a distal portion to afirst solution comprising a plurality of molecules of the formulaX1-J1-M1, wherein X1 and M1 represent separate functional groups and J1represents a spacer moiety that, together, are able to promote formationfrom solution of a self-assembled monolayer for sufficient time to forma monolayer surface having a substantially uniform surface energy on thebase surface,b) removing a portion of the monolayer of step (a) such that a portionof the base surface is again fully or partially exposed,c) exposing the portion of the base surface from (b) to a secondsolution comprising a plurality of molecules of the formula X2-J2-M2 anda plurality of molecules of the formula X1-J1-M1 wherein the functionalgroup M2 has a different surface energy from that of the functionalgroup M1 such that a surface energy gradient from a proximal location toa distal location is formed. The X2 and J2 groups for the molecule inthe second solution can be the same as the X1 and J1 groups for themolecule in the first solution, or they can be different, depending onthe desired final properties of the mixed monolayer.

In another embodiment, removing a portion of the monolayer is done whilethe base surface and monolayer surface are immersed in either the firstsolution or the second solution.

In another embodiment removal of a portion of the monolayer of (a) isperformed using a method or combination of methods selected from thegroup consisting of 1) passing an instrument along the monolayer surfacecreated in (a) with sufficient force to remove a portion of themonolayer created in (a), 2) etching chemically the portion to beremoved, 3) etching physically the portion to be removed, 4) cuttingwith a laser, 5) cutting with water, 6) etching through thermometricexposure, 7) removing with grit, 8) drilling, 9) sonic means, and 10)cutting with an instrument.

In another embodiment, removal of the portion of the monolayer of (a) isperformed while at the same time increasing amounts of a third solutioncomprising a molecule of the formula X2-J2-M2 so that a mixed monolayersurface of M1 and M2 moieties is formed with a molar ratio of M2 to M1that increases from a proximal location to a distal location of thesurface. The X2 and J2 groups for the molecule in the third solution canbe the same as the X1 and J1 groups for the molecule in the firstsolution, or they can be different, depending on the desired finalproperties of the mixed monolayer

In another embodiment, the third solution has a solvent different fromthat of the first solution or the second solution.

In other embodiments, multiple n solutions comprising molecules ofXn-Jn-Mn can be used to create multiple gradients of mixed monolayers.

In several other embodiments, the gradient is created on 1) the insideof a tube, 2) the outside of a tube, 3) on a rectangular channel havingthree walls and one side open, 4) on only 1 face of the channel, 5) on 2faces of the channel, and 6) on 3 faces of the channel.

In another embodiment, the base surface is a metal oxide comprising ametal oxide from the group comprising silica, alumina, quartz, glass, orthe like. In some embodiments using metal oxide base surfaces, thefunctional group X is a carboxylic acid.

In an additional embodiment, the base surface is a metal selected fromthe group comprising gold, silver, copper, aluminum, cadmium, zinc,palladium, platinum, mercury, lead, iron, chromium, manganese, tungsten,and any alloys of the above. In some embodiments using metals for thebase surfaces, the functional group X is a sulfur-containing functionalgroup (e.g.thiols, sulfides, disulfides, and the like). In otherembodiments, the metal of the base surface is in the form of a metalizedfilm coating a polymer surface.

In another embodiment, the base surface is doped or undoped silicon. Insome embodiments using doped or undoped silicon for the base surface,the functional group X is selected from the group comprising silanes orchlorosilanes.

In another embodiment, the base surface is a metal selected from thegroup comprising palladium and platinum. In some embodiments using thesemetals for the base surface, the functional group X is a functionalgroup selected from the group comprising nitrites and isonitriles.

In another embodiment, the base surface is copper. In some embodimentsusing copper for the base surface, the functional group X is ahydroxamic acid.

In another embodiment, the base surface is gold. In some embodimentsusing gold for the base surface, the functional group X is at least onesulfur-containing functional group selected from the group consisting ofthiols, sulfides, or disulfides.

In another embodiment, the functional group M1, M2, . . . Mn is selectedfrom the group comprising ionic, nonionic, polar, nonpolar, halogenated,alkyl, aryl or other functionalities,

In other embodiments, the functional group M1, M2, . . . Mn can includeany one of the following: —OH, —CONHR, —CONHCOR, —NHR, —COOH, —COOR,—CSNHR, —COR, —RCSR, —RSR, —ROR, —SOOR, —RSOR, —CONR₂, —(OCH₂ CH₂)OH,—(OCH₂ CH₂)_(n)OR—CH₃, —NR₂, —CN, —(CF₂)_(n)CF₃, —CO₂CH₃, —CONHCH₃, —CR,CHCH₂, —OCH₂CF₂CF₃, Cl, Br, olefins, and the like, and any combinationthereof .

In the above list, R is hydrogen or an organic group such as ahydrocarbon or fluorinated hydrocarbon. As used herein, the term“hydrocarbon” includes alkyl, alkenyl, alkynyl, cycloalkyl, aryl,alkaryl, aralkyl, and the like. The hydrocarbon group may, for example,comprise methyl, propenyl, ethynyl, cyclohexyl, phenyl, tolyl, andbenzyl groups. The term “fluorinated hydrocarbon” is meant to refer tofluorinated derivatives of the above-described hydrocarbon groups.

In another embodiment, J is a hydrocarbon chain with the formula —(CH₂)—where n is between 1 and 22, preferably between 2 and 18, morepreferably between 2 and 12.

Other embodiments of the invention are 1) a surface that is a surfaceenergy gradient, 2) a surface utilizing a surface energy gradient, 3) asurface that is a surface energy gradient as produced by any of themethods of the claims, and 4) a surface utilizing a surface energygradient as produced by any of the methods of the claims.

Another embodiment of the invention is a surface as produced by any ofthe methods of the claims that is used in lab-on-a-chip technology.

In another embodiment, the monolayer surfaces of channels and passagesare constructed and arranged such that a single drop or multiple dropsof fluid requires less external force to move through channels andpassages with the monolayer surface than channels and passages withoutthe monolayer surface.

In another embodiment, the monolayer surfaces are constructed andarranged such that instead of having separate wells where the fluid isdelivered and analyzed, the analysis could be done while the fluid movesalong the channels. Reactive chemicals can be incorporated into thesurface with the surface energy gradient so that the certain chemicals,proteins, etc. could be detected in the drop as it moves along thesurface.

In another embodiment, the gradient is created on a standardmicromachined array of channels in silicon. Because silicon oxide is ahigh-energy surface, water will wet it very easily, and friction losseswould be high. The high-energy silicon oxide surface can be convertedinto a low-energy surface by depositing a SAM film on the silicon thatwill repel water and reduce friction. Based on the details of theexperiments discussed in the previous section, one preferred SAM wouldbe obtained from an alkylsilane-based surfactant with a silane headgroup X and a methyl (—CH₃) tail group M. The silane head group willbond with the silicon, resulting in a SAM film with a —CH₃ surface. Thecarbon chain backbone of the SAM should be a single chain and contain atleast 12 carbons. This type of SAM will pack very closely, resulting ina lowered friction loss. A molecule with a carbon chain backbone of atleast 6 carbons will still pack tightly as well.

In addition to reducing friction, another use for SAMs is in the area offluid transport. An embodiment of the invention includes a design whichgives a means of transporting liquids across a surface without using anyexternal forces in some instances and reduced external forces in othercases. This self-propulsion of liquid drops allows microfabricatedsystems to be much more efficient.

An embodiment of the inventive method takes advantages of the ability ofSAM films to modify the surface energy of a substrate. By changing thetail group of a SAM from, for example, a —CH₃ group to an —OH or —CO₂Hgroup, the surface can change from a low-energy surface to a high-energysurface. Water will not wet a low-energy surface, but it will wet ahigh-energy surface. Therefore, a surface having a surface energygradient allows water to move across the surface from areas of lowenergy into areas of higher and higher surface energy. Embodiments ofthe SAMs of this invention can be used to create such a surface energygradient.

In an embodiment of the inventive method, a mixed SAM surface is createdon a silicon oxide semiconductor surface using two separate SAMsurfactant solutions, an AFM tip for nanografting, and a flow controllerwith picoliter capability for liquid additions. The system is inventiveand unique in that it creates a fluid-impervious surface with a gradientin surface energies.

In the first step of this embodiment, the semiconductor surface isexposed to a toluene solution containing an octadecyltrichlorosilane(this is the first SAM surfactant solution) capable of forming a SAM onthe surface. FIG. 2 begins with the step at which this SAM surfactantsolution has formed a SAM on the surface. In this example, five hours issufficient to create a modified surface coated with a SAM film that hasa methyl (—CH₃) tail group. This treatment creates a low-energy surfacethat repels water. In this embodiment, good results are obtained whenthe process is performed under an inert atmosphere such as nitrogenalthough it can be carried out under normal atmospheric conditions also.

In a specific embodiment, the surface being treated will remain insolution while an AFM tip passes over the surface and begins to removeparts of the original SAM and expose the original semiconductor surface.At the same time the AFM begins to remove the original SAM film, dropsof toluene solution containing an organotrichlorosilane surfactant witha high-energy tail group such as —CO₂H will be added to the solution Thetwo surfactants (one with the high energy tail group the other with thelow energy tail group) will form a mixed SAM on the area where theinstrument scraped the previous SAM away. The instrument will continueto move along the original surface and remove the original SAM whilemore of the CO₂H-terminated surfactant is added to the solution. Thisprocess can continue along the entire length of the channel; as theinstrument passes along the surface, the concentration ofCO₂H-terminated surfactant continually increases in the solution. As thepercentage of CO₂H-terminated surfactant in solution continuallyincreases, the percentage of CO₂H-groups continually increases in themixed monolayer that forms along the path of the AFM tip. The mixed SAMthat forms will have a continuously increasing —CO₂H concentration atthe surface. Therefore, the surface energy increases along the length ofthe channel.

For One Silicon Embodiment

Octadecyltrichlorosilane (CH₃(CH₂)₁₇SiCl₃) in toluene can be used aslow-energy surfactant (X1-J1-M1) where

M1=CH₃ J1=(CH₂)₁₇ X1=SiCl₃

To create the gradient, a molecule (X2-J2-M2) can be used with anyhigher-energy surface group for M2 (CO₂H, OH, etc. or other moiety thathas a higher surface energy than CH₃). For example, even ═CH₂ has ahigher energy than —CH₃. X2 and J2 can be the same as X1 and J1 in thisembodiment.

For a Gold, Silver, or Copper Embodiment

Dodecanethiol (CH₃(CH₂)₁₁SH) in ethanol used as low-energy surfactant(X1-J1-M1) where

M1=CH₃ J1=(CH₂)₁₁ X1=SH

To create the gradient, another thiol of undecanoic acid (CO₂H(CH₂)₁₀SH)as high-energy surfactant (X2-J2-M2) can be used where

M2=CO₂H J2=(CH₂)₁₀ X2=SH

Additional materials and functional groups suitable for use in thepresent invention can be found in U.S. Pat. No. 5,079,600, issued Jan.7, 1992, and incorporated herein by reference.

The SAM-forming compound may terminate in a second end, opposite to theend bearing the functional group selected to bind to the surfacematerial, with any of a variety of functionalities. That is, thecompound may include a functionality that, when the compound forms a SAMon the surface material, is exposed. Such a functionality may beselected to create a SAM that is hydrophobic, hydrophilic, thatselectively binds various biological or other chemical species, or thelike. Other groups for M are found in columns 8 and 9 of U.S. Pat. No.5,776,748.

U.S. Pat. No. 4,690,715 contains good examples of chemicals to use withdifferent surfaces. Other useful patents are U.S. Pat. Nos. 5,620,850,5,079,600, 5,512,131, 6,235,340. All of the above patents are hereinincorporated by reference.

Another embodiment of an inventive method starts with a silicon orplastic surface that has a gold, silver, or copper coating on it. Withthis system embodiment, thiols could be used instead of silanes andethanol could be used instead of toluene. The process could then takeplace under ambient conditions. Thiols offer more stability than silanesunder many conditions, and ethanol is less hazardous than toluene. Also,the time required to form SAM films on gold, silver, and copper fromthiols in solution is often much shorter than the time required to formSAMs from silanes. It can take as little as five minutes to form SAMfilms on gold surfaces using ethanol solutions containing thiols. Itshould be noted, that other SAM-forming compounds that work similarly tothiols or those having at least one sulfur-containing functional groups(e.g. sulfide or disulfide) can be selected.

Occasionally, trichlorosilanes or thiols with high-energy tail groupsare difficult to synthesize. This method can still be used to create asurface energy gradient by using a trichlorosilane or thiols containinga tail group that has only a slightly higher surface energy than thetail group used in the first step.

The mixed-monolayer film that is formed can be reacted with otherreagents to increase the surface energy gradient. For example, atrichlorosilane or thiols with a ═CH₂ tail group could be used as thesecond surfactant M2 in this example. The resulting surface of —CH₃ and═CH₂ tail groups could undergo a series of reactions to convert the ═CH₂tail groups into —CO₂H groups while leaving the —CH₃ groups unreacted.Thus, this process embodiment allows the surface energy gradient to beincreased further.

In this embodiment of the invention, the resulting surface could allowfor self-propulsion of water or other aqueous fluid or drops thereof.Such a drop of water or other aqueous fluid forms a decreasing contactangle along such a surface and has increasing forces of attraction tosuch a surface along its length. An organic or oil-bearing fluid couldbe propelled in a similar manner by starting with a high-energy surface(such as —CO₂H) and decreasing the surface energy along the length ofthe surface or channel using low-energy groups (such as —CH₃).

In an embodiment using water, if a drop of water is placed at thebeginning of the channel, it will not wet the channel because of thelow-energy methyl surface. However, it is attracted to the slightlyhigher energy surface composed of a mixed methyl and —CO₂H surface. Asthe CO₂H concentration of the surface increases, the force of attractionbetween the water and the surface increases. The contact angle betweenthe advancing drop and the mixed-SAM surface decreases along the lengthof the channel. Therefore, the drop can propel itself across the surfacewithout the use of any external forces. By changing the surfactantadditions so that a surface is created with a surface energy gradientfrom high-surface energy to low-surface energy, the design would allowfor a low-energy nonpolar molecule such as a drop of oil to propelitself across the surface. The design could also be used for systemswhere one merely wishes to reduce the external energy required totransfer a liquid across a surface.

It should be recognized to one skilled in the art that a multitude ofsurfaces and surfactants could be used in combinations to form monolayerfilms. Such combinations are considered covered by this invention. Itshould also be recognized to those skilled in the art that manydifferent instruments capable of operating at the nanoscale-scale andsmaller level can be used with this invention. Such uses are alsocovered by this invention. Means of optimizing this process by adjustingsurfactant concentrations in solution, solutions used, exposure times,instrument speeds, geometries, temperatures, substrates, etc. to fitother systems are covered by this invention.

It should be noted that in another embodiment of the invention, theinstrument that removes the original SAM film can also be used todeliver the mixed-SAM solution to the bare surface. For example, areservoir inside the instrument could contain a mixed-SAM solution. Thissolution could then be delivered to the surface at an increasing rate ofdelivery so that the surface energy gradient is created.

In another embodiment, the mixing of the SAM solutions could take placeinside the reservoir. The composition of the mixed-SAM solution wouldchange as one SAM solution is gradually added to the original solutioninside the reservoir. This solution could then be delivered to thesurface at a constant rate of delivery so that the surface energygradient is created.

In another embodiment, the mixing could take place outside the reservoirand then delivered to the surface by various means, one embodiment ofwhich is through the removal instrument.

In another embodiment, it is not necessary for the reservoir in eitherexample to contain a mixed-SAM solution. It can contain only one SAM insolution. The rate of delivery of this solution could be varied tocreate the surface energy gradient. In another embodiment, the surfaceis used for improving fluid flow in diagnostic systems that incorporatechemical, biological, or genomic sensors on the surface. It is alsouseful in making such systems even smaller and more efficient.

In some preferred embodiments, at least one of the molecules of formula(X-J-M) chosen to form the monolayers is resistant to the adsorption ofbiopolymers such as proteins, enzymes, antibodies, polynucleic acids,cells, and other biological molecules. By the term “resistant to theadsorption of biopolymers” it is meant that the base surface covered bythe monolayer has a reduction in the amount of a biopolymer adsorbed onthe surface, when contacted with a medium containing biopolymersavailable for adsorption, as compared to the amount adsorbed on the samebase surface that is not covered by the mono layer.

For these embodiments, the J group of the molecule is a spacer moietycomprising a biopolymer-resistant domain. Suitable moieties for thebiopolymer-resistant domain of the J group are discussed in U.S. Pat.No. 6,235,340 and include oligoethers, oligo glycols, oligoalcohols,oligo carbonyls, oligo sulfides, oligosulfones and oligosaccharides.Such moieties typically are used to produce a monolayer that is bothhydrophilic and biopolymer-resistant.

In one embodiment, the biopolymer-resistant domain comprises anoligo-(ethylene glycol) linkage (—OCH₂CH₂—)_(n) where n is 2 to 4.

For embodiments with monolayers (either mixed or uniform) comprisingbiopolymer resistant molecules, the surface to be treated may be ablood-contacting surface, or it may be some other type of surface, e.g.the surface of a biosensor, bioseparation chamber, or the surface of anelectronic device or component or of an electrochemical detection oranalysis device. It may be a surface of a finished device such as ablood-contacting device or it may be the surface of a material to beused in forming a finished device. In the latter case subsequent formingsteps are selected to avoid disrupting the coating formed by the processof the invention in portions of the device where the coating willprotect the surface in use and to avoid chemical damage, for instancedue to high temperatures, to the coating. Such coated surfaces thereforehave applications in blood contacting devices and in devices wherereduced non-specific protein adsorption is desirable, for instance indiagnostic devices which require a specific interaction of an analyteand detector species, e.g. biosensors, bioseparation membranes and sightcorrection devices.

In one embodiment, the invention can be used for improving medical orlaboratory devices to increase biocompatibility and resistance toprotein binding.

In another embodiment, the surface gradient is created on DNA microarrayslides. Current slides are composed of single strands of DNA attached ona glass slide to form discrete dots in an array pattern. Several hundredor more dots currently can be put on a slide. A solution containingsingle strands of DNA is poured on top of the slide. The DNA strands insolution eventually match up to the matching stationary strand on theslide. Because the slides are manufactured so that the specific locationand composition of the stationary strand is known, one can determine theDNA make-up of the solution by identifying where the DNA couplingreaction occurs.

A further embodiment of this invention, would improve the fluidtransport across the slide. Instead of waiting for the DNA strands todiffuse through solution until it finds its matching strand, the fluidis directed across the slide so that it is distributed more efficiently.This would also make the slides much smaller. Rather than having strandsin dots, they could be in a series of lines along the surface. As thefluid moves across the surface due to the surface energy gradient, theDNA will react to the matching strand as it passes over it.

Another embodiment is the use of this surface in miniaturized systemsthat require cooling. The fluid is transported through coolant channelsusing the surface energy gradient. Reducing the surface tension of afluid allows it to flow into regions of smaller and smaller dimensions.Any type of semiconductor, electromechanical, or optoelectronic devicethat requires cooling to operate the most efficiently could use thistechnology. The invention would also allow such systems to be made evensmaller because the size of the device would not face the heat transferlimitations that many current devices have.

Another embodiment is the use of the surface gradient in medicaldevices, treatments and artificial organs. Small tubes with a surfaceenergy gradient on the inside surface are able to function ascapillaries or other blood vessels. The blood would naturally flowthrough the tube; surface tension would not prevent it from moving intorecesses and other extremely small openings.

Another embodiment is the use of the surface gradient in depositingmetal or other components on hard to reach and surfaces in corners ordeep recesses. For example, an electroless plating solution could betransported to an inside corner deep within an object using thisinvention. Metal could then be deposited in an area that was previouslyunable to be coated.

Another embodiment is the use of the surface gradient in not only justusing these systems to merely detect and analyze solutions, thisinvention can be used in objects and devices that actually treat and/ordeliver medical benefits. For instance, a vein or artery surface (eithernatural or artificial) could be treated so that it has a surface energygradient that causes plaque or cholesterol particles to be transportedto specific areas where they are reacted with a component that destroysthem in solution. This would prevent cholesterol from building up on thewalls.

Another embodiment is the use of the surface gradient in integrationwith biopharmaceutical molecules that recognize a certain genetic orprotein sequence. When virus or cancer or other disease moleculescontaining that sequence are transported across the surface, thereactive chemical recognizes the sequence of interest and kills theharmful molecule.

FIG. 2 shows a blown-up schematic view of the method during the removaland exposure steps wherein the instrument 11 that removes the SAM layer3 also delivers new molecules 13 to the base surface 1. In this mannerthe mixing of first molecules 5 and second molecules 13 is performednear the base surface 1 as the instrument 11 delivers second molecules13 from the instrument reservoir 21. The instrument 11 can have the newmolecules 13 stored in the instrument reservoir 21 inside the instrument11 or added to the instrument 11 by tool 23 as the instrument 11 passesalong the surface 1.

FIG. 3 shows a blown-up schematic view of the method during the removaland exposure steps wherein the instrument 11 that removes the SAM layer3 also delivers new molecules 13 to the base surface 1. In this mannerthe mixing of first molecules 5 and second molecules 13 is performedinside the instrument reservoir 21 and then the mixture is deliverednear the base surface 1 as the instrument 11 delivers second molecules13 from the instrument reservoir 21. The instrument 11 can have the newmolecules 13 stored in the instrument reservoir 21 inside the instrument11 or added to the instrument 11 by tool 23 as the instrument 11 passesalong the surface 1.

FIG. 4 illustrates another method of mixing. Here, the mixing method hassimilarities to those illustrated in FIG. 2 and FIG. 3, However themixing of molecules is performed in an outside reservoir 25. The mixedmolecules are then transferred into the instrument reservoir 21 by meansof a line 27.

In FIG. 5, the mixed-SAM surface 29 reacts with NHS (N-hydroxysuccinimide) to produce a surface with an increasing concentration ofNHS ester (step b). It should be noted that the portions of the CH₃—CO₂Hmixed monolayer that do not take part in the reaction are not shown(e.g. CH₃). Various proteins 31 containing lysine groups can then beadsorbed by NHS-surfaces 33 (step c). The NHS-surface 33 functions toself-propel or reduce the external force requirements necessary forpropulsion of a liquid (e.g. blood) while removing protein moleculesfrom the liquid. Similar designs could have a wide application inanalyzing blood, other protein-bearing liquids, and liquids containingoligo-strands of DNA, as well as antigen/antibody combinations. ThisNHS-surface and other such surfaces use SAM surfaces such as these, withproperties tailored to adsorb specific molecules, and provides means toeffectively decrease the necessary dimensions of such analyticalsystems. This system could also be applied to stent technology so as toremove harmful proteins or fats from collecting in arteries and othersuch body lumens.

FIG. 6 illustrates a method for creating a surface energy gradient onthe inside of a tube 35. In this instance, the instrument 11 is incontact with the uniform surface energy monolayer on the inside walls ofthe tube 35 and moves along the inside of the tube 35 in a directionlongitudinal to the longitudinal axis 37 removing the uniform surfaceenergy monolayer. The second organic molecules having a differentfunctional group than that of the removed monolayer can be in solutionabove the instrument in upper area 39, below in lower area 41, or inboth upper area 39 or lower area 41. The solution can also flow througha hollow cavity in the instrument 11 so as to reach the surface to betreated. As more second organic molecules are added a greater numberwill react with the portion of the tube which has had the uniformsurface energy monolayer removed. In this way a longitudinal gradient iscreated on the inside walls of the tube 35.

FIG. 7 illustrates a similar method for creating a surface energygradient on the inside of a tube 35. However, in this instance, theinstrument 11 is in contact with the uniform surface energy monolayer onthe inside walls of the tube 35 and moves along the inside of the tube35 in a rotational direction about the longitudinal axis 37 removing theuniform surface energy monolayer. The second organic molecules having adifferent functional group than that of the removed monolayer can be insolution above the instrument in upper area 39, below in lower area 41,or in both upper area 39 and lower area 41. The solution can also flowthrough a hollow cavity in the instrument 11 so as to reach the surfaceto be treated. As more second organic molecules are added a greaternumber will react with the portion of the tube which has had theeuniform surface energy monolayer removed. In this way a gradient iscreated on the inside walls of the tube 35 about a strip on the radius.

FIG. 8 illustrates a schematic of the pattern of surface energy gradient43 created if the instrument 11 from FIG. 7 is in contact with theuniform surface energy monolayer on the inside walls of the tube 35 andmoves along the inside of the tube 35 in a rotational direction aboutthe longitudinal axis 37 and in a longitudinal direction along thelongitudinal axis 37 removing the uniform surface energy monolayer. Thesecond organic molecules having a different functional group than thatof the removed monolayer can be in solution above the instrument inupper area 39, below in lower area 41, or in both upper area 39 or lowerarea 41. The solution can also flow through a hollow cavity in theinstrument 11 so as to reach the surface to be treated As more secondorganic molecules are added a greater number will react with the portionof the tube which has had the uniform surface energy monolayer removed.In this way a gradient is created on the inside walls of the tube 35 ina spiral type pattern.

FIG. 9 illustrates a method for creating a surface energy gradient onthe outside side of a tube 35. In this instance, the instrument 11 is incontact with the uniform surface energy monolayer on the outside wallsof the tube 35 and moves along the outside of the tube 35 in a directionlongitudinal to the longitudinal axis 37 removing the uniform surfaceenergy monolayer. The direction of the instrument's movement can also berotational about the longitudinal axis 37 or a combination of rotationaland longitudinal movement thereby creating a spiral gradient on theoutside of the tube. The second organic molecules having a differentfunctional group than that of the removed monolayer can be in solutionabove the longitudinal instrument contact point 45 in upper area 39,below in lower area 41, or in both upper area 39 or lower area 41. Thesolution can also flow through a hollow cavity in the instrument 11 soas to reach the surface to be treated. As more second organic moleculesare added a greater number will react with the portion of the tube whichhas had the uniform surface energy monolayer removed. In this way agradient is created on the outside walls of the tube 35.

FIGS. 10 and 11 illustrate how the surface energy gradient can becreated on only specific portions of the tube. By employing the samemethods and mechanisms as those of FIGS. 6, 7, 8, and 9 with theaddition of teeth or tips 47 even more specific portions of surfaceenergy gradient can be created on the inside of the tube 35 as in FIG.10 and the outside of the tube as in FIG. 11.

While this invention may be embodied in many different forms, there aredescribed in detail herein specific preferred embodiments of theinvention. This description is an exemplification of the principles ofthe invention and is not intended to limit the invention to theparticular embodiments illustrated.

For the purposes of this disclosure, like reference numerals in thefigures shall refer to like features unless otherwise indicated.

The above disclosure is intended to be illustrative and not exhaustive.This description will suggest many variations and alternatives to one ofordinary skill in this art. All these alternatives and variations areintended to be included within the scope of the claims where the term“comprising” means “including, but not limited to”. Those familiar withthe art may recognize other equivalents to the specific embodimentsdescribed herein which equivalents are also intended to be encompassedby the claims.

Further, the particular features presented in the dependent claims canbe combined with each other in other manners within the scope of theinvention such that the invention should be recognized as alsospecifically directed to other embodiments having any other possiblecombination of the features of the dependent claims. For instance, forpurposes of claim publication, any dependent claim which follows shouldbe taken as alternatively written in a multiple dependent form from allprior claims which possess all antecedents referenced in such dependentclaim if such multiple dependent format is an accepted format within thejurisdiction (e.g. each claim depending directly from claim 1 should bealternatively taken as depending from all previous claims). Injurisdictions where multiple dependent claim formats are restricted, thefollowing dependent claims should each be also taken as alternativelywritten in each singly dependent claim format which creates a dependencyfrom a prior antecedent-possessing claim other than the specific claimlisted in such dependent claim below.

This completes the description of the preferred and alternateembodiments of the invention. Those skilled in the art may recognizeother equivalents to the specific embodiment described herein whichequivalents are intended to be encompassed by the claims attachedhereto.

Such information as may be found relating to portions of thisapplication include:

-   -   Kataoka, Dawn E. and Troian, Sandra M., “Patterning Liquid Flow        on the Microscopic Scale,” Nature, Vol. 402, December 1999, pp.        794-797.    -   Kim, H., Graupe, M., Oloba, O., Koini, T., Imaduddin, S., Lee,        T., and Perry, S., “Molecularly Specific Studies of the        Frictional Properties of Monolayer Films: A Systematic        Comparison of CF3—, (CH3)2CH—, and CH3-Terminated Films,”        Langmuir, 1999, Vol. 15, pp. 3179-3185.    -   Krim, J. “Atomic-Scale Origins of Friction,” Langmuir, 1996,        Vol. 12, pp. 4564-4566.    -   Laibinis, P., Palmer, B., Lee, S., and Jennings, G. K., “The        Synthesis of Organothiols and Their Assembly into Monolayers on        Gold, ” Thin Films Vol. 24, 1998.    -   Laibinis, P., Fox, M., Folkers, J., and Whitesides, G.,        “Comparisons of Self-Assembled Monolayers on Silver and Gold,”        Langmuir, 1991, Vol. 7, pp. 3167-3173.    -   Lee, S., Shon, Y., Colorado, R., Guenard, R., Lee, T., and        Perry, S., “The Influence of Packing Densities and Surface Order        on the Frictional Properties of Alkanethiol Self-Assembled        Monolayers (SAMs) on Gold, Langmuir, 2000, Vol. 16, pp.        2220-2224.    -   Liu, Y. and Evans, D., “Structure and Frictional Properties of        Self-assembled Surfactant Monolayers,” Langmuir, 1996, Vol. 12,        pp. 1235-1244.    -   Patel, N., Davies, M., Hartshorne, M., Heaton, R., Roberts, C.,        Tendler, S., and Williams, P., “Immobilization of Protein        Molecules onto Homogenous and Mixed Carboxylate-Terminated        Self-Assembled Monolayers,” Langmuir, 1997, Vol. 13, pp.        6485-6490.    -   Pfahler, J, Harley, J., and Bau, H., “Liquid Transport in Micron        and Submicron Channels,” Sensors and Actuators, A21-23, 1990,        pp. 431-434.    -   Tsukruk, V., and Bliznyuk, V., “Adhesive and Friction Forces        Between Chemically Modified Silicon and Silicon Nitride        Surfaces, ” Langmuir, 1998, Vol. 14, pp. 446-455.    -   Xiao, X., Hu, J., Charych, D., and Salmeron, M., “Chain Length        Dependence of the Frictional Properties of Alkylsilane Molecules        Self-Assembled on Mica Studied by Atomic Force Microscopy,”        Langmuir, 1996, Vol. 12, pp.235-237.    -   Xu, S., Miller, S., Laibinis, P, and Liu, G., “Fabrication of        Nanometer Scale Patterns within Self-Assembled Monolayers by        Nanografting,” Langmuir, 1999, Vol. 15, pp. 7244-7251.    -   U.S. Pat. No. 6,235,340    -   U.S. Pat. No. 5,512,131    -   U.S. Pat. No. 5,776,748    -   U.S. Pat. No. 4,690,715    -   U.S. Pat. No. 5,620,850    -   U.S. Pat. No. 5,079,600

All US patents and applications and all other published documentsmentioned anywhere in this application are incorporated herein byreference in their entirety.

1) A medical device comprising at least one distinct region of length Land width W of the surface of the device covered by a mixed monolayerfilm, the mixed monolayer film comprising a species having a functionalgroup M1 and a species having a functional group M2 where M1 and M2 havedifferent surface energies, the mixed monolayer forming a surface energygradient from a proximal location to a distal location within the regionwherein L equals the distance from the proximal location to the distallocation, W is 20 nanometers or greater, and the ratio of L/W is greaterthan 2 and wherein at least one of the species comprises abiopolymer-resistant domain. 2) The device of claim 1, wherein the mixedmonolayer is formed from species X1-J1-M1 and X2-J2-M2 wherein X1, X2,M1, and M2 represent separate functional groups where M1 and M2 havedifferent surface energies and J1 and J2 represents spacer moieties, thespecies X1-J1-M1 and X2-J2-M2 forming a self-assembled monolayer ontothe base surface from solution. 3) The device of claim 1 wherein themolar concentration of the species comprising the functional group M2continuously increases relative to the concentration of the speciescomprising functional group M1 from the proximal location to the distallocation of the region having the mixed monolayer. 4) The device ofclaim 1 wherein any portions of the surface that border the at least onedistinct region along the dimension l have substantially equal surfaceenergies: 5) The device of claim 4 wherein any portions of the surfacethat border the at least one distinct region along the dimension L arecovered by substantially uniform monolayers. 6) The device of claim 5wherein the substantially uniform monolayers comprisebiopolymer-resistant domains. 7) The device of claim 1 wherein thebiopolymer-resistant domain comprises an oligo-(ethylene glycol)linkage. 8) The device of claim 6 wherein the biopolymer-resistantdomain comprises an oligo-(ethylene glycol) linkage. 9) The device ofclaim 1 where the ratio of L/W is greater than
 10. 10) An analyticaldevice comprising a fluid-impervious surface comprising a base surface,at least one distinct region of length L and width W of the base surfacecovered by a mixed monolayer film, the mixed monolayer film comprising aspecies having a functional group M1 and a species having a functionalgroup M2 where M1 and M2 have different surface energies, the mixedmonolayer forming a surface energy gradient from a proximal location toa distal location within the region wherein L equals the distance fromthe proximal location to the distal location, W is 20 nanometers orgreater, and the ratio of L/W is greater than 2 and wherein at least oneof the species comprises a biopolymer-resistant domain and wherein atleast one of the regions comprising the surface energy gradient isdefined in a series of channels and passages. 11) The device of claim10, wherein the mixed monolayer is formed from species X1-J1-M1 andX2-J2-M2 wherein X1, X2, M1, and M2 represent separate functional groupswhere M1 and M2 have different surface energies and J1 and J2 representsspacer moieties, the species X1-J1-M1 and X2-J2-M2 forming aself-assembled monolayer onto the base surface from solution. 12) Thedevice of claim 10 wherein any portions of the surface that border theat least one distinct region along the dimension L have substantiallyequal surface energies 13) The device in claim 10, wherein the surfacegradient of channels and passages are constructed and arranged such thatfluid requires less external energy to move through channels andpassages with the surface gradient than channels and passages withoutthe surface gradient. 14) The device in claim 10, wherein the surfacegradients are constructed and arranged to deliver fluid to separatewells for analysis. 15) The device in claim 10, wherein the surfacegradients comprise reactive chemicals for detecting the presence ofchemical species, proteins, and the like as the fluid moves along thesurface. 16) The device of claim 12 wherein any portions of the surfacethat border the at least one distinct region along the dimension L arecovered by substantially uniform monolayers. 17) The device of claim 16wherein the substantially uniform monolayers comprisebiopolymer-resistant domains. 18) The device of claim 17 wherein thebiopolymer-resistant domain comprises an oligo-(ethylene glycol)linkage. 19) The device of claim 10 wherein the biopolymer-resistantdomain comprises an oligo-(ethylene glycol) linkage.